WO2021092407A1 - Inhibiteurs d'entrée virale de la grippe - Google Patents

Inhibiteurs d'entrée virale de la grippe Download PDF

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Publication number
WO2021092407A1
WO2021092407A1 PCT/US2020/059442 US2020059442W WO2021092407A1 WO 2021092407 A1 WO2021092407 A1 WO 2021092407A1 US 2020059442 W US2020059442 W US 2020059442W WO 2021092407 A1 WO2021092407 A1 WO 2021092407A1
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compound
influenza
pharmaceutically acceptable
nmr
mhz
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PCT/US2020/059442
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English (en)
Inventor
Lijun RONG
Irina GAISINA
Gregory R. Thatcher
Norton Peet
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The Board Of Trustees Of The University Of Illinois
Chicago Biosolutions, Inc.
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Application filed by The Board Of Trustees Of The University Of Illinois, Chicago Biosolutions, Inc. filed Critical The Board Of Trustees Of The University Of Illinois
Priority to AU2020378084A priority Critical patent/AU2020378084A1/en
Priority to EP20885338.2A priority patent/EP4054551A4/fr
Priority to CA3160645A priority patent/CA3160645A1/fr
Publication of WO2021092407A1 publication Critical patent/WO2021092407A1/fr
Priority to US17/735,235 priority patent/US11787769B2/en
Priority to GB2206782.1A priority patent/GB2605040B/en

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/21—Esters, e.g. nitroglycerine, selenocyanates
    • A61K31/215—Esters, e.g. nitroglycerine, selenocyanates of carboxylic acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/58—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems with hetero atoms directly attached to the ring nitrogen atom
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/44—Non condensed pyridines; Hydrogenated derivatives thereof
    • A61K31/445—Non condensed piperidines, e.g. piperocaine
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/435—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having six-membered rings with one nitrogen as the only ring hetero atom
    • A61K31/47—Quinolines; Isoquinolines
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K45/00—Medicinal preparations containing active ingredients not provided for in groups A61K31/00 - A61K41/00
    • A61K45/06—Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
    • A61P31/12—Antivirals
    • A61P31/14—Antivirals for RNA viruses
    • A61P31/16—Antivirals for RNA viruses for influenza or rhinoviruses
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D207/00—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D207/02—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D207/04—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D207/10—Heterocyclic compounds containing five-membered rings not condensed with other rings, with one nitrogen atom as the only ring hetero atom with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D207/14—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/02—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom condensed with one carbocyclic ring
    • C07D209/04—Indoles; Hydrogenated indoles
    • C07D209/30—Indoles; Hydrogenated indoles with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, directly attached to carbon atoms of the hetero ring
    • C07D209/40—Nitrogen atoms, not forming part of a nitro radical, e.g. isatin semicarbazone
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D209/00—Heterocyclic compounds containing five-membered rings, condensed with other rings, with one nitrogen atom as the only ring hetero atom
    • C07D209/56—Ring systems containing three or more rings
    • C07D209/96—Spiro-condensed ring systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/08—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms
    • C07D211/18—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms
    • C07D211/26—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hydrocarbon or substituted hydrocarbon radicals directly attached to ring carbon atoms with substituted hydrocarbon radicals attached to ring carbon atoms with hydrocarbon radicals, substituted by nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D211/00—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings
    • C07D211/04—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom
    • C07D211/06—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members
    • C07D211/36—Heterocyclic compounds containing hydrogenated pyridine rings, not condensed with other rings with only hydrogen or carbon atoms directly attached to the ring nitrogen atom having no double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D211/56—Nitrogen atoms
    • C07D211/58—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D215/00—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems
    • C07D215/02—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom
    • C07D215/16—Heterocyclic compounds containing quinoline or hydrogenated quinoline ring systems having no bond between the ring nitrogen atom and a non-ring member or having only hydrogen atoms or carbon atoms directly attached to the ring nitrogen atom with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D215/38—Nitrogen atoms
    • C07D215/42—Nitrogen atoms attached in position 4
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D223/00—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom
    • C07D223/02—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings
    • C07D223/06—Heterocyclic compounds containing seven-membered rings having one nitrogen atom as the only ring hetero atom not condensed with other rings with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D223/12—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D241/00—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings
    • C07D241/02—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings
    • C07D241/04—Heterocyclic compounds containing 1,4-diazine or hydrogenated 1,4-diazine rings not condensed with other rings having no double bonds between ring members or between ring members and non-ring members
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
    • C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
    • C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
    • C07D498/10—Spiro-condensed systems

Definitions

  • BACKGROUND Seasonal or pandemic flu is an infectious disease that is mainly caused by influenza A viruses (IAV).
  • Influenza A virus is under continuous evolvement due to antigenic mutation, adaptation, and reassortment, and highly virulent strains may appear unexpectedly to produce epidemics or pandemics.
  • Vaccination remains the principal prophylactic for controlling influenza infections 1-3 although its efficacy is limited during a pandemic.
  • NAIs neuraminidase inhibitors
  • zanamivir zanamivir
  • peramivir The neuraminidase inhibitors
  • influenza M2 ion channel blockers amantadine and rimantadine
  • the efficacy of the NAIs has also been undermined by resistance. 12-14 More importantly, during the 2008-2009 influenza season, almost all seasonal influenza A/H 1 N 1 isolates in the US were resistant to oseltamivir (99%, compared to 11% in 2007-2008).
  • pandemic 2009 influenza A/H 1 N 1 virus and the highly pathogenic avian influenza (HPAI) H 5 N 1 strains have been generally susceptible to NAIs; 18-21 however, oseltamivir resistant strains have been isolated from patients infected with both of these strains. 18-23 Therefore, NAIs may not be sufficient for use alone in future influenza pandemics. Additional therapeutic agents with a new mechanism of action that are effective in treating influenza virus, either alone or in combination with other drugs are in great need.
  • SUMMARY Vaccination is the most prevalent prophylactic means for controlling seasonal influenza infections. However, an effective vaccine usually takes at least 6 months to develop for the circulating strains.
  • Described herein are fast-acting, orally active acylated amino-substituted heterocyclyl compounds effective to control this virus.
  • X is CH or N; ring A is a nitrogen-containing heterocyclyl; R h is alkyl or cycloalkyl; R d is one to nine substituents independently selected from alkyl, halo, haloalkyl, aryl, arylalkyl and C 3 -C 5 cycloalkyl; R f is selected from H, alkyl, aryl, and arylalkyl; and R e is one to five substituents independently selected from halo, haloalkyl, aryl, arylalkyl and –NO 2 .
  • described herein is a composition comprising a compound of formula I and a pharmaceutically acceptable excipient.
  • described herein is a method of treating an influenza infection in a subject comprising administering to the subject a compound of formula I.
  • described herein is a method of treating an influenza infection in a subject comprising administering to the subject a compound of formula I and a neuraminidase inhibitor.
  • the compounds described herein act as potent inhibitors of the oseltamivir- resistant influenza A (H 1 N 1 ) virus strain with the most common H274Y resistance mutation.
  • FIG.1 shows an infectious virus replication inhibition assay.
  • H 1 N 1 (A/Puerto Rico/8/1934) (A) or H 5 N 1 (A/Vietnam/1203/2004) (B) viruses at the MOI of 0.01 were used to infect A549 cells in the presence or absence of selected 4-aminopiperidines at the 1 and 10 ⁇ M concentrations.
  • viral titers were determined by the standard plaque assay in MDCK cells. The assay was performed in triplicate; results are presented as mean ⁇ SD.
  • the term “about” is used to provide flexibility to a numerical range endpoint by providing that a given value may be “a little above” or “a little below” the endpoint without affecting the desired result.
  • “about” refers to a range extending from 10% below the numerical value to 10% above the numerical value. For example, if the numerical value is 10, “about 10” means between 9 and 11 inclusive of the endpoints 9 and 11
  • “Admixing” or “admixture” refers to a combination of two components together when there is no chemical reaction or physical interaction.
  • the terms “admixing” and “admixture” can also include the chemical interaction or physical interaction among any of the components described herein upon mixing to produce the composition.
  • the components can be admixed alone, in water, in another solvent, or in a combination of solvents.
  • subject as defined herein is any organism in need of treatment and/or prevention (e.g., infection, inflammation, etc.).
  • the subject is a mammal including, but not limited to, humans, domesticated animals (e.g., dogs, cats, horses), livestock (e.g., cows, pigs), and wild animals.
  • references in the specification and concluding claims to parts by weight, of a particular element in a composition or article denote the weight relationship between the element or component and any other elements or components in the composition or article for which a part by weight is expressed.
  • X and Y are present at a weight ratio of 2:5, and are present in such a ratio regardless of whether additional components are contained in the compound.
  • a weight percent of a component is based on the total weight of the formulation or composition in which the component is included.
  • each of the combinations A + E, A + F, B + D, B + E, B + F, C + D, C + E, and C + F is specifically contemplated and should be considered from disclosure of A, B, and C; D, E, and F; and the example combination of A + D.
  • any subset or combination of these is also specifically contemplated and disclosed.
  • Alkenyl means a straight or branched chain hydrocarbon containing from 2 to 10 carbons, unless otherwise specified, and containing at least one carbon-carbon double bond.
  • Representative examples of alkenyl include, but are not limited to, ethenyl, 2-propenyl, 2-methyl- 2-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl, 2-heptenyl, 2-methyl-1-heptenyl, 3-decenyl, and 3,7-dimethylocta-2,6-dienyl.
  • Alkoxy means an alkyl group, as defined herein, appended to the parent molecular moiety through an oxygen atom.
  • alkoxy include, but are not limited to, methoxy, ethoxy, propoxy, 2-propoxy, butoxy, tert-butoxy, pentyloxy, and hexyloxy.
  • Alkyl means a straight or branched chain hydrocarbon containing from 1 to 10 carbon atoms unless otherwise specified. The alkyl may be substituted with one or more groups selected from halo, hydroxy, alkoxy, cyano, amino, carboxyl and carboxyalkyl.
  • alkyl include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso- butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, n-hexyl, 3-methylhexyl, 2,2-dimethylpentyl, 2,3- dimethylpentyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.
  • an “alkyl” group is a linking group between two other moieties, then it may also be a straight or branched chain; examples include, but are not limited to -CH 2 -, -CH 2 CH 2 -, -CH 2 CH 2 CHC(CH 3 )-, and -CH 2 CH(CH 2 CH 3 )CH 2 -.
  • “Aryl” means a phenyl (i.e., monocyclic aryl), or a bicyclic ring system containing at least one phenyl ring or an aromatic bicyclic ring containing only carbon atoms in the aromatic bicyclic ring system. In certain embodiments of the disclosure, the aryl group is phenyl or naphthyl.
  • the aryl is substituted with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, -CN, -CO 2 H, -SO 2 R h , -SO 2 NHR h , -NHSO 2 R h and heterocyclyl wherein R h is alkyl.
  • the aryl is phenyl.
  • Arylalkyl means an aryl group as defined herein connected to the parent molecular moiety through an alkylene group.
  • An exemplary arylalkyl group is benzyl.
  • Cyano and “nitrile” mean a -CN group.
  • Cycloalkyl means a monocyclic or a bicyclic cycloalkyl ring system.
  • Monocyclic ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain embodiments, cycloalkyl groups are fully saturated. Examples of monocyclic cycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl.
  • Bicyclic cycloalkyl ring systems are bridged monocyclic rings or fused bicyclic rings.
  • Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH 2 ) w -, where w is 1, 2, or 3).
  • alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH 2 ) w -, where w is 1, 2, or 3).
  • Representative examples of bicyclic ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane.
  • Fused bicyclic cycloalkyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl.
  • the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.
  • the cycloalkyl is substituted with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, -CN, -CO2H, -SO2Rh, -SO2NHRh, -NHSO2Rh and heterocyclyl wherein R h is alkyl.
  • the cycloalkyl is a C 3 -C 5 cycloalkyl.
  • “Nitrogen-containing hetercyclyl” means a monocyclic or a bicyclic cycloalkyl ring system where one or more of the carbon atoms of the cycloalkyl ring is substituted with nitrogen.
  • Monocyclic nitrogen-containing hetercyclyl ring systems are cyclic hydrocarbon groups containing from 3 to 8 carbon atoms and one or more nitrogen atoms, where such groups can be saturated or unsaturated, but not aromatic. In certain aspects, the nitrogen-containing hetercyclyl groups are fully saturated. Examples of monocyclic nitrogen-containing hetercyclyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl, where one or more carbon atoms is substituted with nitrogen.
  • Bicyclic nitrogen-containing hetercyclyl ring systems are bridged monocyclic rings or fused bicyclic rings.
  • Bridged monocyclic rings contain a monocyclic cycloalkyl ring where two non-adjacent carbon atoms of the monocyclic ring are linked by an alkylene bridge of between one and three additional carbon atoms (i.e., a bridging group of the form -(CH 2 ) w -, where w is 1, 2, or 3).
  • bicyclic nitrogen-containing hetercyclyl ring systems include, but are not limited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane, bicyclo[2.2.2]octane, bicyclo[3.2.2]nonane, bicyclo[3.3.1]nonane, and bicyclo[4.2.1]nonane, where one or more carbon atoms are substituted with nitrogen.
  • Fused bicyclic nitrogen-containing hetercyclyl ring systems contain a monocyclic cycloalkyl ring fused to either a phenyl, a monocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclic heteroaryl, where one or more carbon atoms are substituted with nitrogen.
  • the bridged or fused bicyclic cycloalkyl is attached to the parent molecular moiety through any carbon atom contained within the monocyclic cycloalkyl ring.
  • the nitrogen-containing hetercyclyl is substituted with one or more groups selected from alkyl, cycloalkyl, cycloalkylalkyl, halo, haloalkyl, -CN, -CO 2 H, -SO 2 R j , -SO 2 NHR j , -NHSO 2 R j and heterocyclyl wherein R j is alkyl.
  • the cycloalkyl is a C 3 -C 5 cycloalkyl.
  • the nitrogen-containing hetercyclyl selected from tetrahyroquinolyl, indolyl, indolinyl and piperidinyl;
  • Halo or “halogen” means -Cl, -Br, -I or -F.
  • Haloalkyl means at least one halogen, as defined herein, appended to the parent molecular moiety through an alkyl group, as defined herein.
  • Representative examples of haloalkyl include, but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl, pentafluoroethyl, and 2-chloro-3-fluoropentyl.
  • each “haloalkyl” is a fluoroalkyl, for example, a polyfluoroalkyl such as a substantially perfluorinated alkyl.
  • saturated as used herein means the referenced chemical structure does not contain any multiple carbon-carbon bonds.
  • a saturated cycloalkyl group as defined herein includes cyclohexyl, cyclopropyl, and the like.
  • Unsaturated means the referenced chemical structure contains at least one multiple carbon-carbon bond, but is not aromatic.
  • an unsaturated cycloalkyl group as defined herein includes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like.
  • “Pharmaceutically acceptable salts” refers to salts or zwitterionic forms of the present compounds. Salts of the present compounds can be prepared during the final isolation and purification of the compounds or separately by reacting the compound with an acid having a suitable cation.
  • the pharmaceutically acceptable salts of the present compounds can be acid addition salts formed with pharmaceutically acceptable acids. Examples of acids which can be employed to form pharmaceutically acceptable salts include inorganic acids such as nitric, boric, hydrochloric, hydrobromic, sulfuric, and phosphoric, and organic acids such as oxalic, maleic, succinic, tartaric, and citric.
  • Nonlimiting examples of salts of compounds of the disclosure include, but are not limited to, the hydrochloride, hydrobromide, hydroiodide, sulfate, bisulfate, 2- hydroxyethansulfonate, phosphate, hydrogen phosphate, acetate, adipate, alginate, aspartate, benzoate, bisulfate, butyrate, camphorate, camphorsulfonate, digluconate, glycerolphosphate, hemisulfate, heptanoate, hexanoate, formate, succinate, fumarate, maleate, ascorbate, isethionate, salicylate, methanesulfonate, mesitylenesulfonate, naphthylenesulfonate, nicotinate, 2- naphthalenesulfonate, oxalate, pamoate, pectinate, persulfate, 3-phenylproprionate, picrate, pi
  • available amino groups present in the compounds of the disclosure can be quaternized with methyl, ethyl, propyl, and butyl chlorides, bromides, and iodides; dimethyl, diethyl, dibutyl, and diamyl sulfates; decyl, lauryl, myristyl, and stearyl chlorides, bromides, and iodides; and benzyl and phenethyl bromides.
  • any reference to compounds of the present disclosure appearing herein is intended to include the present compounds as well as pharmaceutically acceptable salts thereof.
  • MSA Bismuth sulfite agar
  • CI Combination Index
  • DMEM Dulbecco's Modified Eagle Medium
  • eGFP enhanced green fluorescent protein
  • ESI electrospray ionization
  • HA hemagglutinin
  • HPAI highly pathogenic avian influenza
  • IAV influenza A virus
  • LC-MSD liquid chromatography/mass selective detector
  • LM liver microsomes
  • MDCK Madin-Darby canine kidney
  • MOI multiplicity of infection
  • NADPH nicotinamide adenine dinucleotide phosphate, reduced form
  • NAI neuraminidase inhibitor
  • PBS phosphate buffered saline
  • STAB sodium triacetoxyborohydride
  • TLC thin layer chromatography
  • TPCK N-p-tosyl-L-phenylalanine chloromethyl ketone.
  • HA hemagglutinin
  • 24-27 HA is an attractive target because it is involved in the first step in viral entry and because HA-neutralizing antibodies are protective. 1, 27-31
  • the HA inhibitors described herein may be used alone, or in combination with NAIs to treat infections by H 1 N 1 and H 5 N 1 .
  • the compounds described herein or a pharmaceutically acceptable salt thereof have the structure I wherein X is CH or N; ring A is a nitrogen-containing hetercyclyl; R h is alkyl or cycloalkyl; Rd is one to nine substituents independently selected from alkyl, halo, haloalkyl, aryl, arylalkyl and C 3 -C 5 cycloalkyl; R f is selected from H, alkyl, aryl, and arylalkyl; and R e is one to five substituents independently selected from halo, haloalkyl, aryl, arylalkyl and –NO 2 .
  • the compounds described herein or a pharmaceutically acceptable salt thereof have the structure II wherein X is CH or N; ring A is a nitrogen-containing hetercyclyl selected from tetrahyroquinolyl, indolyl, indolinyl and piperidinyl; R a , R b and R c are independently selected from H, alkyl and aryl, or any two of Ra, Rb and Rc, together with the C atom to which they are attached define a cycloalkyl; R d is one to nine substituents independently selected from alkyl, halo, haloalkyl, aryl, arylalkyl and C 3 -C 5 cycloalkyl; R f is selected from H, alkyl, aryl, and arylalkyl; and R e is one to five substituents independently selected from halo, haloalkyl, aryl, arylalkyl and –NO 2 .
  • the compound of formula I is selected from wherein Rg is one to four substituents independently selected from halo, haloalkyl, aryl, arylalkyl and C 3 -C 5 cycloalkyl, or a pharmaceutically acceptable salt thereof.
  • X is CH.
  • R f is H.
  • R e is selected from –NO 2 , Cl and –CF 3 .
  • Rd is selected from H and halo and Rg is selected from H, halo, haloalkyl and C 3 -C 5 cycloalkyl.
  • halo is F and haloalkyl is CF 3 .
  • the compound of formula I is selected from wherein Rg is one to four substituents independently selected from halo, haloalkyl, aryl, arylalkyl and C 3 -C 5 cycloalkyl, or a pharmaceutically acceptable salt thereof.
  • X is CH.
  • R f is H.
  • the compound of formula I is selected from
  • the compound has the structure wherein R e is haloalkyl, X is CH, and n is 1 to 4. In another aspect, R e is haloalkyl, X is CH, and R f is H. In another aspect, R e is haloalkyl, X is CH, R f is H, and R h is an alkyl. In another aspect, n is 1. In another aspect, R e is CF 3 . In another aspect, R e is at the 4 position of the aryl ring. In another aspect, R h is a tert-butyl group or an isopropyl group.
  • described herein is a method of treating an individual suffering from an influenza infection comprising administering a compound of structural formula (I) to an individual in need thereof.
  • the methods described herein relate to the use of a compound of formula I and an optional second therapeutic agent useful in the treatment of an influenza infection.
  • the methods described herein can be accomplished by administering a compound of formula (I) as the neat compound or as a pharmaceutical composition. Administration of a pharmaceutical composition, or a neat compound of structural formula (I), can be performed during or after the onset of the disease or condition of interest.
  • a compound of formula I is administered in conjunction with a second therapeutic agent useful in the treatment of influenza infections.
  • the second therapeutic agent is different from the compound of formula I.
  • a compound of structural formula I and the second therapeutic agent can be administered simultaneously or sequentially.
  • a compound of formula I and the second therapeutic agent can be administered from a single composition or two separate compositions.
  • a compound of formula I and the second therapeutic agent can be administered simultaneously or sequentially to achieve the desired effect.
  • the second therapeutic agent includes a neuraminidase inhibitor.
  • Neuraminidase inhibitors are a class of drugs which block the neuraminidase enzyme. They are commonly used as antiviral drugs because they block the function of viral neuraminidases of the influenza virus, by preventing its reproduction by budding from the host cell.
  • Oseltamivir Teamiflu
  • Zanamivir Relenza
  • Laninamivir Inavir
  • Peramivir belong to this class.
  • one or more neuraminidase inhibitors can be administered in conjunction with the compounds described herein.
  • the second therapeutic agent is administered in an amount to provide its desired therapeutic effect.
  • the effective dosage range for each second therapeutic agent is known in the art, and the second therapeutic agent is administered to an individual in need thereof within such established ranges.
  • Treating” or “treatment” includes the treatment of a disease or disorder described herein, in a subject, preferably a human, and includes: i. inhibiting a disease or disorder, i.e., arresting its development; ii. relieving a disease or disorder, i.e., causing regression of the disorder; iii. slowing progression of the disorder; and/or iv. inhibiting, relieving, or slowing the onset or progression of one or more symptoms of the disease or disorder.
  • “Therapeutically effective amount” refers to an amount that is sufficient to achieve the desired therapeutic result or to have an effect on undesired symptoms, but is generally insufficient to cause adverse side effects.
  • the specific therapeutically effective dose level for any particular patient will depend upon a variety of factors including the disorder being treated and the severity of the disorder; the specific composition employed; the age, body weight, general health, sex and diet of the patient; the time of administration; the route of administration; the rate of excretion of the specific compound employed; the duration of the treatment; drugs used in combination or coincidental with the specific compound employed and like factors within the knowledge and expertise of the health practitioner and which may be well known in the medical arts.
  • the desired response can be inhibiting the progression of the disease or condition. This may involve only slowing the progression of the disease temporarily. However, in other instances, it may be desirable to halt the progression of the disease permanently. This can be monitored by routine diagnostic methods known to one of ordinary skill in the art for any particular disease.
  • the desired response to treatment of the disease or condition also can be delaying the onset or even preventing the onset of the disease or condition.
  • the effective daily dose can be divided into multiple doses for purposes of administration. Consequently, single dose compositions can contain such amounts or submultiples thereof to make up the daily dose.
  • the dosage can be adjusted by the individual physician in the event of any contraindications. It is generally preferred that a maximum dose of the pharmacological agents described herein (alone or in combination with other therapeutic agents) be used, that is, the highest safe dose according to sound medical judgment. It will be understood by those of ordinary skill in the art however, that a patient may insist upon a lower dose or tolerable dose for medical reasons, psychological reasons or for virtually any other reasons.
  • a response to a therapeutically effective dose of a disclosed compound and/or pharmaceutical composition can be measured by determining the physiological effects of the treatment or medication, such as the decrease or lack of disease symptoms following administration of the treatment or pharmacological agent.
  • Other assays will be known to one of ordinary skill in the art and can be employed for measuring the level of the response.
  • the amount of a treatment may be varied for example by increasing or decreasing the amount of a disclosed compound and/or pharmaceutical composition, by changing the disclosed compound and/or pharmaceutical composition administered, by changing the route of administration, by changing the dosage timing and so on. Dosage can vary, and can be administered in one or more dose administrations daily, for one or several days. Guidance can be found in the literature for appropriate dosages for given classes of pharmaceutical products.
  • “Prophylactically effective amount” refers to an amount effective for preventing onset or initiation of a disease or condition.
  • Prevent or “preventing” refers to precluding, averting, obviating, forestalling, stopping, or hindering something from happening, especially by advance action. It is understood that where reduce, inhibit or prevent are used herein, unless specifically indicated otherwise, the use of the other two words is also expressly disclosed.
  • “Second therapeutic agent” refers to a therapeutic agent different from a compound of formula I and that is known to treat the disease or condition of interest.
  • the second therapeutic agent may be an agent used to treat influenza infections.
  • the second therapeutic agent is a neuraminidase inhibitor is oseltamivir, zanamivir, peramivir, or a pharmaceutically acceptable salt thereof, and any combination thereof.
  • Constant administration means that two or more agents are administered concurrently to the subject being treated.
  • concurrently it is meant that each agent is administered either simultaneously or sequentially in any order at different points in time. However, if not administered simultaneously, it is meant that they are administered to an individual in a sequence and sufficiently close in time so as to provide the desired therapeutic effect and can act in concert.
  • a compound of structural formula (I) can be administered at the same time or sequentially in any order at different points in time as a second therapeutic agent.
  • a present compound and the second therapeutic agent can be administered separately, in any appropriate form and by any suitable route.
  • “Pharmaceutically acceptable” describes a material that is not biologically or otherwise undesirable, i.e., without causing an unacceptable level of undesirable biological effects or interacting in a deleterious manner.
  • “Pharmaceutically acceptable vehicle” refers to a diluent, adjuvant, excipient or carrier with which a compound of the disclosure is administered.
  • the terms “effective amount” or “pharmaceutically effective amount” refer to a nontoxic but sufficient amount of the agent to provide the desired biological result. That result can be reduction and/or alleviation of the signs, symptoms, or causes of a disease, or any other desired alteration of a biological system.
  • An appropriate “effective” amount in any individual case can be determined by one of ordinary skill in the art using routine experimentation.
  • “Pharmaceutically acceptable carriers” for therapeutic use are well known in the pharmaceutical art, and are described, for example, in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).
  • sterile saline and phosphate-buffered saline at physiological pH can be used.
  • Preservatives, stabilizers, dyes and even flavoring agents can be provided in the pharmaceutical composition.
  • sodium benzoate, sorbic acid and esters of p-hydroxybenzoic acid can be added as preservatives. Id. at 1449.
  • antioxidants and suspending agents can be used. Id.
  • Contacting refers to bringing a disclosed compound or pharmaceutical composition in proximity to a cell, a target protein, or other biological entity together in such a manner that the disclosed compound or pharmaceutical composition can affect the activity of the a cell, target protein, or other biological entity, either directly; i.e., by interacting with the cell, target protein, or other biological entity itself, or indirectly; i.e., by interacting with another molecule, co-factor, factor, or protein on which the activity of the cell, target protein, or other biological entity itself is dependent.
  • compositions comprising a therapeutically effective amount of one or more compounds described herein and one or more pharmaceutically acceptable diluents, preservatives, solubilizers, emulsifiers, adjuvants, excipients, or carriers.
  • the pharmaceutical composition can be used, for example, for treating diseases or conditions characterized by allergic inflammation.
  • Suitable excipients for non-liquid formulations are also known to those of skill in the art. A thorough discussion of pharmaceutically acceptable excipients and salts is available in Remington’s Pharmaceutical Sciences, 18th Edition (Easton, Pennsylvania: Mack Publishing Company, 1990).
  • a biological buffer can be any solution which is pharmacologically acceptable and which provides the formulation with the desired pH, i. e. , a pH in the physiologically acceptable range.
  • buffer solutions include saline, phosphate buffered saline, Tris buffered saline, Hank’s buffered saline, and the like.
  • the pharmaceutical compositions can be in the form of solid, semi-solid or liquid dosage forms, such as, for example, tablets, suppositories, pills, capsules, powders, liquids, suspensions, creams, ointments, lotions or the like, preferably in unit dosage form suitable for single administration of a precise dosage.
  • the compositions will include an effective amount of the selected drug in combination with a pharmaceutically acceptable carrier and, in addition, can include other pharmaceutical agents, adjuvants, diluents, buffers, and the like.
  • compositions of the disclosure will be administered in a therapeutically effective amount by any of the accepted modes of administration. Suitable dosage ranges depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, the indication towards which the administration is directed, and the preferences and experience of the medical practitioner involved.
  • One of ordinary skill in the art of treating such diseases will be able, without undue experimentation and in reliance upon personal knowledge and the disclosure of this application, to ascertain a therapeutically effective amount of the compositions of the disclosure for a given disease.
  • compositions of the disclosure can be administered as pharmaceutical formulations including those suitable for oral (including buccal and sub-lingual), rectal, nasal, topical, pulmonary, vaginal or parenteral (including intramuscular, intra-arterial, intrathecal, subcutaneous and intravenous) administration or in a form suitable for administration by inhalation or insufflation.
  • conventional nontoxic solid carriers include, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharin, talc, cellulose, glucose, sucrose, magnesium carbonate, and the like.
  • Liquid pharmaceutically administrable compositions can, for example, be prepared by dissolving, dispersing, and the like, an active compound as described herein and optional pharmaceutical adjuvants in an excipient, such as, for example, water, saline, aqueous dextrose, glycerol, ethanol, and the like, to thereby form a solution or suspension.
  • the pharmaceutical composition to be administered can also contain minor amounts of nontoxic auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.
  • auxiliary substances such as wetting or emulsifying agents, pH buffering agents and the like, for example, sodium acetate, sorbitan monolaurate, triethanolamine sodium acetate, triethanolamine oleate, and the like.
  • permeation enhancer excipients including polymers such as: poly cations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine, chitosan- thiogly colic acid, chitosan-glutathione conjugates).
  • polymers such as: poly cations (chitosan and its quaternary ammonium derivatives, poly-L-arginine, aminated gelatin); polyanions (N-carboxymethyl chitosan, poly-acrylic acid); and, thiolated polymers (carboxymethyl cellulose-cysteine, polycarbophil-cysteine, chitosan-thiobutylamidine,
  • the composition will generally take the form of a tablet, capsule, a softgel capsule or can be an aqueous or nonaqueous solution, suspension or syrup. Tablets and capsules are preferred oral administration forms. Tablets and capsules for oral use can include one or more commonly used carriers such as lactose and corn starch. Lubricating agents, such as magnesium stearate, are also typically added.
  • the compositions of the disclosure can be combined with an oral, non-toxic, pharmaceutically acceptable, inert carrier such as lactose, starch, sucrose, glucose, methyl cellulose, magnesium stearate, dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like.
  • suitable binders include starch, gelatin, natural sugars such as glucose or beta-lactose, corn sweeteners, natural and synthetic gums such as acacia, tragacanth, or sodium alginate, carboxymethylcellulose, polyethylene glycol, waxes, and the like.
  • Lubricants used in these dosage forms include sodium oleate, sodium stearate, magnesium stearate, sodium benzoate, sodium acetate, sodium chloride, and the like.
  • Disintegrators include, without limitation, starch, methyl cellulose, agar, bentonite, xanthan gum, and the like.
  • the active agent can be combined with any oral, non toxic, pharmaceutically acceptable inert carrier such as ethanol, glycerol, water, and the like and with emulsifying and suspending agents. If desired, flavoring, coloring and/or sweetening agents can be added as well.
  • suitable inert carrier such as ethanol, glycerol, water, and the like
  • flavoring, coloring and/or sweetening agents can be added as well.
  • Other optional components for incorporation into an oral formulation herein include, but are not limited to, preservatives, suspending agents, thickening agents, and the like.
  • Parenteral formulations can be prepared in conventional forms, either as liquid solutions or suspensions, solid forms suitable for solubilization or suspension in liquid prior to injection, or as emulsions.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • the acceptable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Parenteral administration includes intraarticular, intravenous, intramuscular, intradermal, intraperitoneal, and subcutaneous routes, and include aqueous and non-aqueous, isotonic sterile injection solutions, which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient, and aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • aqueous and non-aqueous, isotonic sterile injection solutions which can contain antioxidants, buffers, bacteriostats, and solutes that render the formulation isotonic with the blood of the intended recipient
  • aqueous and non-aqueous sterile suspensions that can include suspending agents, solubilizers, thickening agents, stabilizers, and preservatives.
  • Administration via certain parenteral routes can involve introducing the formulations of the disclosure into the body of a patient through a needle or a catheter, propelled by a sterile syringe or some other mechanical device such as a continuous infusion system.
  • a formulation provided by the disclosure can be administered using a syringe, injector, pump, or any other device recognized in the art for parenteral administration.
  • sterile injectable suspensions are formulated according to techniques known in the art using suitable carriers, dispersing or wetting agents and suspending agents.
  • the sterile injectable formulation can also be a sterile injectable solution or a suspension in a nontoxic parenterally acceptable diluent or solvent.
  • Suitable vehicles and solvents that can be employed are water, Ringer’s solution and isotonic sodium chloride solution.
  • sterile, fixed oils, fatty esters or polyols are conventionally employed as solvents or suspending media.
  • parenteral administration can involve the use of a slow release or sustained release system such that a constant level of dosage is maintained.
  • Preparations according to the disclosure for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, or emulsions.
  • non-aqueous solvents or vehicles are propylene glycol, polyethylene glycol, vegetable oils, such as olive oil and corn oil, gelatin, and injectable organic esters such as ethyl oleate.
  • Such dosage forms can also contain adjuvants such as preserving, wetting, emulsifying, and dispersing agents. They can be sterilized by, for example, filtration through a bacteria retaining filter, by incorporating sterilizing agents into the compositions, by irradiating the compositions, or by heating the compositions. They can also be manufactured using sterile water, or some other sterile injectable medium, immediately before use.
  • Sterile injectable solutions are prepared by incorporating one or more of the compounds of the disclosure in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filtered sterilization.
  • dispersions are prepared by incorporating the various sterilized active ingredients into a sterile vehicle which contains the basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum-drying and freeze-drying techniques which yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile- filtered solution thereof.
  • a parenteral composition suitable for administration by injection is prepared by stirring 1.5% by weight of active ingredient in 10% by volume propylene glycol and water. The solution is made isotonic with sodium chloride and sterilized.
  • compositions of the disclosure can be administered in the form of suppositories for rectal administration.
  • suppositories for rectal administration.
  • suppositories can be prepared by mixing the agent with a suitable nonirritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the drug.
  • suitable nonirritating excipient include cocoa butter, beeswax and polyethylene glycols.
  • Ointments are semisolid preparations which are typically based on petrolatum or other petroleum derivatives.
  • Creams containing the selected active agent are, as known in the art, viscous liquid or semisolid emulsions, either oil-in-water or water-in-oil.
  • Cream bases are water-washable, and contain an oil phase, an emulsifier and an aqueous phase.
  • the oil phase also sometimes called the “internal” phase, is generally comprised of petrolatum and a fatty alcohol such as cetyl or stearyl alcohol; the aqueous phase usually, although not necessarily, exceeds the oil phase in volume, and generally contains a humectant.
  • the emulsifier in a cream formulation is generally a nonionic, anionic, cationic or amphoteric surfactant.
  • the specific ointment or cream base to be used is one that will provide for optimum drug delivery.
  • an ointment base should be inert, stable, nonirritating and nonsensitizing.
  • Formulations for buccal administration include tablets, lozenges, gels and the like.
  • buccal administration can be affected using a transmucosal delivery system as known to those skilled in the art.
  • the compounds of the disclosure can also be delivered through the skin or mucosal tissue using conventional transdermal drug delivery systems, i.e., transdermal “patches” wherein the agent is typically contained within a laminated structure that serves as a drug delivery device to be affixed to the body surface.
  • the drug composition is typically contained in a layer, or “reservoir,” underlying an upper backing layer.
  • the laminated device can contain a single reservoir, or it can contain multiple reservoirs.
  • the reservoir comprises a polymeric matrix of a pharmaceutically acceptable contact adhesive material that serves to affix the system to the skin during drug delivery.
  • suitable skin contact adhesive materials include, but are not limited to, polyethylenes, polysiloxanes, polyisobutylenes, polyacrylates, polyurethanes, and the like.
  • the drug-containing reservoir and skin contact adhesive are present as separate and distinct layers, with the adhesive underlying the reservoir which, in this case, can be either a polymeric matrix as described above, or it can be a liquid or gel reservoir, or can take some other form.
  • the backing layer in these laminates which serves as the upper surface of the device, functions as the primary structural element of the laminated structure and provides the device with much of its flexibility.
  • the material selected for the backing layer should be substantially impermeable to the active agent and any other materials that are present.
  • compositions of the disclosure can also be administered by nasal aerosol or inhalation.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, propellants such as fluorocarbons or nitrogen, and/or other conventional solubilizing or dispersing agents.
  • compositions of the disclosure can be formulated for aerosol administration, particularly to the respiratory tract and including intranasal administration.
  • Such compositions are prepared according to techniques well-known in the art of pharmaceutical formulation and can be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, and/or other conventional solubilizing or dispersing agents.
  • the compound will generally have a small particle size for example of the order of 5 microns or less. Such a particle size can be obtained by means known in the art, for example by micronization.
  • the active ingredient is provided in a pressurized pack with a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • a suitable propellant such as a chlorofluorocarbon (CFC) for example dichlorodifluoromethane, trichlorofluoromethane, or dichlorotetrafluoroethane, carbon dioxide or other suitable gas.
  • CFC chlorofluorocarbon
  • the aerosol can conveniently also contain a surfactant such as lecithin.
  • the dose of drug can be controlled by a metered valve.
  • the active ingredients can be provided in a form of a dry powder, for example a powder mix of the compound in a suitable powder base such as lactose, starch, starch derivatives such as hydroxypropylmethyl cellulose and polyvinylpyrrol
  • a pharmaceutically or therapeutically effective amount of a compound described herein will be delivered to the subject.
  • the precise effective amount will vary from subject to subject and will depend upon the species, age, the subject’s size and health, the nature and extent of the condition being treated, recommendations of the treating physician, and the therapeutics or combination of therapeutics selected for administration. Thus, the effective amount for a given situation can be determined by routine experimentation.
  • the subject can be administered as many doses as is required to reduce and/or alleviate the signs, symptoms, or causes of the disorder in question, or bring about any other desired alteration of a biological system.
  • formulations can be prepared with enteric coatings adapted for sustained or controlled release administration of the active ingredient.
  • the pharmaceutical preparations are preferably in unit dosage forms.
  • the preparation is subdivided into unit doses containing appropriate quantities of the active component.
  • the unit dosage form can be a packaged preparation, the package containing discrete quantities of preparation, such as packeted tablets, capsules, and powders in vials or ampoules.
  • the unit dosage form can be a capsule, tablet, cachet, or lozenge itself, or it can be the appropriate number of any of these in packaged form.
  • kits whereby two or more components, which may be active or inactive ingredients, carriers, diluents, and the like, are provided with instructions for preparation of the actual dosage form by the patient or person administering the drug to the patient.
  • Such kits may be provided with all necessary materials and ingredients contained therein, or they may contain instructions for using or making materials or components that must be obtained independently by the patient or person administering the drug to the patient.
  • a kit can include optional components that aid in the administration of the unit dose to patients, such as vials for reconstituting powder forms, syringes for injection, customized IV delivery systems, inhalers, etc.
  • kits can contain instructions for preparation and administration of the compositions.
  • the kit can be manufactured as a single use unit dose for one patient, multiple uses for a particular patient (at a constant dose or in which the individual compounds may vary in potency as therapy progresses); or the kit may contain multiple doses suitable for administration to multiple patients (“bulk packaging”).
  • the kit components may be assembled in cartons, blister packs, bottles, tubes, and the like.
  • kits can be packaged in a daily dosing regimen (e.g., packaged on cards, packaged with dosing cards, packaged on blisters or blow-molded plastics, etc.). Such packaging promotes products and increases patient compliance with drug regimens. Such packaging can also reduce patient confusion.
  • the kits further contain instructions for use.
  • the present disclosure also provides a pharmaceutical pack or kit comprising one or more containers filled with one or more of the ingredients of the pharmaceutical compositions described herein. Associated with such container(s) can be a notice in the form prescribed by a governmental agency regulating the manufacture, use or sale of pharmaceuticals or biological products, which notice reflects approval by the agency of manufacture, use or sale for human administration.
  • kits can also comprise compounds and/or products co- packaged, co-formulated, and/or co-delivered with other components.
  • a drug manufacturer, a drug reseller, a physician, a compounding shop, or a pharmacist can provide a kit comprising a disclosed compound and/or product and another component for delivery to a patient. It is contemplated that the disclosed kits can be used in connection with the disclosed methods of making, the disclosed methods of using or treating, and/or the disclosed compositions.
  • ASPECTS Aspect 1 ASPECTS Aspect 1.
  • a compound of formula I or a pharmaceutically acceptable salt thereof wherein X is CH or N; ring A is a nitrogen-containing hetercyclyl; R h is alkyl or cycloalkyl; Rd is one to nine substituents independently selected from alkyl, halo, haloalkyl, aryl, arylalkyl and C 3 -C 5 cycloalkyl; R f is selected from H, alkyl, aryl, and arylalkyl; and R e is one to five substituents independently selected from halo, haloalkyl, aryl, arylalkyl and –NO 2 .
  • Aspect 2 Aspect 2.
  • X is CH or N
  • ring A is a nitrogen-containing hetercyclyl selected from tetrahyroquinolyl, indolyl, indolinyl and piperidinyl
  • R a , R b and R c are independently selected from H, alkyl and aryl, or any two of R a , R b and R c , together with the C atom to which they are attached define a cycloalkyl
  • R d is one to nine substituents independently selected from alkyl, halo, haloalkyl, aryl, arylalkyl and C 3 -C 5 cycloalkyl
  • R f is selected from H, alkyl, aryl, and arylalkyl
  • R e is one to five substituents independently selected from halo, haloalkyl, aryl, arylalkyl and
  • Rg is one to four substituents independently selected from halo, haloalkyl, aryl, arylalkyl and C 3 -C 5 cycloalkyl, or a pharmaceutically acceptable salt thereof.
  • Aspect 4. The compound of any one of Aspects 1-3 or a pharmaceutically acceptable salt thereof, wherein X is CH.
  • Aspect 5. The compound of any one of Aspects 1-4 or a pharmaceutically acceptable salt thereof, wherein R f is H.
  • Aspect 6. The compound of any one of Aspects 1-5 or a pharmaceutically acceptable salt thereof, wherein R e is selected from –NO 2 , Cl and –CF 3 .
  • Aspect 8 The compound of any one of Aspects 1-6 or a pharmaceutically acceptable salt thereof, wherein Rd is selected from H and halo and Rg is selected from H, halo, haloalkyl and C 3 -C 5 cycloalkyl.
  • Aspect 8 The compound of any one of Aspects 1-7 or a pharmaceutically acceptable salt thereof, wherein halo is F and haloalkyl is CF 3 .
  • Aspect 9 The compound of Aspect 1, wherein the compound has the structure wherein R e is haloalkyl, X is CH, and n is 1 to 4.
  • Aspect 10 The compound of Aspect 9, wherein R e is haloalkyl, X is CH, and R f is H.
  • Aspect 9 The compound of Aspect 9, wherein R e is haloalkyl, X is CH, R f is H, and R h is an alkyl group.
  • Aspect 12 The compound of any one of Aspects 9-11, wherein n is 1.
  • Aspect 13 The compound of any one of Aspects 9-12, wherein R e is CF 3 .
  • Aspect 14 The compound of any one of Aspects 9-13, wherein R e is at the 4 position of the aryl ring.
  • Aspect 15 The compound of any one of Aspects 9-14, wherein R h is a tert-butyl group or an isopropyl group.
  • Aspect 16 The compound of Aspect 1 selected from
  • Aspect 18 A composition comprising a compound of any one of Aspects 1-17 and a pharmaceutically acceptable excipient.
  • Aspect 19 A method of treating an influenza infection in a subject comprising administering to the subject a compound of any one of Aspects 1-17.
  • Aspect 20 The method of Aspect 19 further comprising administering to the subject a neuraminidase inhibitor.
  • Aspect 21 The method of Aspect 20, wherein the neuraminidase inhibitor comprises oseltamivir, zanamivir, peramivir, or a pharmaceutically acceptable salt thereof.
  • reaction conditions e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures, and other reaction ranges and conditions
  • reaction conditions e.g., component concentrations, desired solvents, solvent mixtures, temperatures, pressures, and other reaction ranges and conditions
  • Only reasonable and routine experimentation will be required to optimize such process conditions.
  • Compounds described herein may be prepared as shown in Scheme 1, where we used the Schotten-Baumann reaction to produce the desired benzoylated amines.
  • Scheme 1 the synthesis of compound 1 is shown as an example, prepared from 2,6-dichlorobenzoyl chloride (35) and 4- amino-1-isopropylpiperidine (36).
  • Scheme 1 Synthesis of acylated 4-aminopiperidines (as shown for hit compound 1).
  • Table 6 Synergistic anti-influenza activity of oseltamivir carboxylate (OC) and ING- 14-66. Based on its superior potency in the infectious strain, we prioritized compound 16 for hepatic metabolic stability testing in liver microsomes (LM). The percentages of compound remaining after 60 minutes of incubation in both mouse and human LM in the presence of NADPH oxidase were 94% and 97%, respectively, indicating excellent metabolic stability.
  • Pharmacokinetic analysis of the plasma and liver levels of ING-14-66 in BALB/c mice following i.p. administration or gavage (p.o.) indicated that the maximal levels are rapidly reached, with T max 30 min (Table 7). The C max level in the plasma with the 10 mg/kg i.p.
  • Low-passage A549 cells were infected with influenza A virus (HA of H5N1, Goose/ Qinghai/59/ 05 ) following a previously published protocol 32 in the presence and absence of compounds at 12.5 ⁇ M. Plates were incubated for 48 h and the infection was then quantified by the lucif erase activity of the infected A549 cells using the Neolite Reporter Gene Assay System (Perkin Elmer; Boston, MA). Compounds that showed >80% inhibition at 12.5 ⁇ M concentration were further evaluated to determine their EC50 values using four-parameter logistic regression analysis in GraphPad Prism (Graphpad Software; San Diego, CA).
  • Madin-Darby canine kidney (MDCK) epithelial cells were grown in Dulbecco’s modified Eagle’s medium (DMEM; Cellgro, Manassas, VA, USA) supplemented with 10% fetal bovine serum (FBS; Gibco, Carlsbad, CA, USA), 1000 units/mL penicillin, and 100 ⁇ g/mL of streptomycin (Invitrogen, Carlsbad, CA, USA).
  • DMEM Dulbecco’s modified Eagle’s medium
  • FBS Gibco, Carlsbad, CA, USA
  • penicillin Gibco, Carlsbad, CA, USA
  • streptomycin 100 ⁇ g/mL of streptomycin
  • Antiviral determination was performed using reporter PR8-PB2-Gluc virus as previously described. 41 Briefly, MDCK cells grown in 96-well plates were infected with IAV PR8-PB2-Gluc at an MOI of 0.01 TCID50/cell, in absence or presence of increasing concentrations of test compound. After lh incubation at 37 °C, the inoculums were removed and cells were washed with PBS. Fresh Opti-MEM containing 2 ⁇ g/ml TPCK-trypsin were added for culture.
  • MDCK cells growing in 24 well plates were infected by PR8-NSl-Gluc at an MOI of 0.01. After 1 h incubation at 37 °C, cells were washed and treated with serial concentrations of compounds alone or in combination. At 48-hr post infection, the virus replication was monitored by luciferase assay using BioLux Gaussia Luciferase Assay Kit (NEB, Ipswich, MA, USA) as previously described. 42 Data were analyzed according to the method of Chou-Talalay 39 .
  • the EC30, EC40, EC50, EC60, EC70, EC80 and EC90 values were chosen for comparison.
  • ECx,A and ECx,B are the concentrations for single agent to achieve the same effect.
  • Influenza virus H 1 N 1 (A/Puerto Rico/8/1934) or H 5 N 1 (A/Vietnam/1203/2004; Low pathogenic) were incubated with indicated amounts of compound at room temperature for 30 min. Subsequently, the mixture was added to A549 cells seeded in 12- well plates (3 x 105 cells/well) a day prior to infection and incubated at 37 °C for 1 h. After that, the mixture was removed and the cells were washed with PBS to remove unbound virus. The cells were incubated with DMEM - 0.2 BSA media supplemented, containing 1 ⁇ g of TPCK trypsin (Sigma).

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Abstract

La vaccination est le moyen prophylactique le plus répandu pour lutter contre des infections saisonnières de la grippe. Cependant, un vaccin efficace nécessite généralement au moins 6 mois pour développer les souches circulantes. Par conséquent, de nouvelles options thérapeutiques sont nécessaires pour le traitement aigu d'infections de la grippe pour lutter contre ce virus et pour empêcher le développement de situations épidémiques/pandémiques. L'invention concerne donc des composés hétérocyclyle amino-substitués acylés à action rapide, actifs par voie orale, efficaces pour lutter contre ce virus. Selon un aspect, l'invention concerne une méthode de traitement d'une infection de la grippe chez un sujet consistant à administrer au sujet les composés décrits dans la description.
PCT/US2020/059442 2019-11-07 2020-11-06 Inhibiteurs d'entrée virale de la grippe WO2021092407A1 (fr)

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EP4054551A4 (fr) 2024-03-20
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